Atherosclerosis, a major disease of the elderly, involves both proliferative, as well as degenerative changes in arteries. We originally hypothesized that the control of proliferation of vascular SMCs (SMC) is distrubed with aging, resulting in excessive proliferative responses. The evidence to date indicates that the proliferation of vascular SMCs is significantly increased for old animals in three experimental paradigms: following 1) arterial injury, 2) aortic transplantation of old to young, 3) serum- free culture of SMC in vitro. This data strongly suggests an autocrine basis for the old/young disparity. SMC from old animals show enhanced proliferation compared to young SMC, probably due to production by old SMC of a PDGF-like growth factor. In addition, old SMC produce less growth inhibitory substances that young SMC. Exogenous heparin corrects the imbalance, suggesting that normal mitogenic signals are 'disinhibited' with aging. We propose to examine systemically the effects of purified mitogens and inhibitors or the growth of old and young SMC in vitro. Age-related proliferative changes will be examined at the biochemical and molecular level, with special attention directed at the abnormal expression of autrocrine growth factor genes (c- sis and PDGF A-chain). We will also extend our animal model to include studies of in vivo arterial injury; comparing in young and old animals the rates of reendothelialization, extracellular matrix composition, inhibitory effect of non-anticoagulant heparins, as well as the proliferative properties of EC and SMC in vitro. Both normolipemic and hypercholesterolmic subjects will be examined, thereby expanding our understanding of the interaction of other atherogenic risk factors in this model. The proposed studies are directed toward elucidation of the molecular control of SMC proliferation during the aging process.